Systematic Gene Overexpression in Candida albicans identifies a Regulator of Early Adaptation to the Mammalian Gut

Sadri Znaidi, Lasse van Wijlick, Arturo Hernández-Cervantes, Natacha Sertour, Jean‐Luc Desseyn, Frédéric Vincent, Ralitsa Atanassova, Valérie Gouyer, Carol A. Munro, Sophie Bachellier-Bassi, Frédéric Dalle, Thierry Jouault, Marie-Elisabeth Bougnoux, Christophe d'Enfert (Corresponding Author)

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Abstract

Candida albicans is part of the human gastrointestinal (GI) microbiota. To better understand how C. albicans efficiently establishes GI colonization, we competitively challenged growth of 572 signature‐tagged strains (~10% genome coverage), each conditionally overexpressing a single gene, in the murine gut. We identified CRZ2, a transcription factor whose overexpression and deletion respectively increased and decreased early GI colonization. Using clues from genome‐wide expression and gene‐set enrichment analyses, we found that the optimal activity of Crz2p occurs under hypoxia at 37°C, as evidenced by both phenotypic and transcriptomic analyses following CRZ2 genetic perturbation. Consistent with early colonization of the GI tract, we show that CRZ2 overexpression confers resistance to acidic pH and bile salts, suggesting an adaptation to the upper sections of the gut. Genome‐wide location analyses revealed that Crz2p directly modulates the expression of many mannosyltransferase‐ and cell‐wall protein‐encoding genes, suggesting a link with cell‐wall function. We show that CRZ2 overexpression alters cell‐wall phosphomannan abundance and increases sensitivity to tunicamycin, suggesting a role in protein glycosylation. Our study reflects the powerful use of gene overexpression as a complementary approach to gene deletion to identify relevant biological pathways involved in C. albicans interaction with the host environment.
Original languageEnglish
Article number12890
JournalCellular Microbiology
Volume20
Issue number11
Early online date7 Aug 2018
DOIs
Publication statusPublished - Nov 2018

Fingerprint

Candida albicans
Mannosyltransferases
Genes
Tunicamycin
Gene Deletion
Bile Acids and Salts
Glycosylation
Gastrointestinal Tract
Transcription Factors
Genome
Growth

Keywords

  • Candida albicans
  • gastrointestinal colonization
  • signature-tagged overexpression
  • transcriptomics
  • chromatin immunoprecipitation-on-chip
  • regulatory networks
  • CRZ2

Cite this

Znaidi, S., van Wijlick, L., Hernández-Cervantes, A., Sertour, N., Desseyn, JL., Vincent, F., ... d'Enfert, C. (2018). Systematic Gene Overexpression in Candida albicans identifies a Regulator of Early Adaptation to the Mammalian Gut. Cellular Microbiology, 20(11), [12890]. https://doi.org/10.1111/cmi.12890

Systematic Gene Overexpression in Candida albicans identifies a Regulator of Early Adaptation to the Mammalian Gut. / Znaidi, Sadri; van Wijlick, Lasse; Hernández-Cervantes, Arturo; Sertour, Natacha; Desseyn, Jean‐Luc; Vincent, Frédéric; Atanassova, Ralitsa; Gouyer, Valérie; Munro, Carol A.; Bachellier-Bassi, Sophie; Dalle, Frédéric; Jouault, Thierry; Bougnoux, Marie-Elisabeth; d'Enfert, Christophe (Corresponding Author).

In: Cellular Microbiology, Vol. 20, No. 11, 12890, 11.2018.

Research output: Contribution to journalArticle

Znaidi, S, van Wijlick, L, Hernández-Cervantes, A, Sertour, N, Desseyn, JL, Vincent, F, Atanassova, R, Gouyer, V, Munro, CA, Bachellier-Bassi, S, Dalle, F, Jouault, T, Bougnoux, M-E & d'Enfert, C 2018, 'Systematic Gene Overexpression in Candida albicans identifies a Regulator of Early Adaptation to the Mammalian Gut', Cellular Microbiology, vol. 20, no. 11, 12890. https://doi.org/10.1111/cmi.12890
Znaidi S, van Wijlick L, Hernández-Cervantes A, Sertour N, Desseyn JL, Vincent F et al. Systematic Gene Overexpression in Candida albicans identifies a Regulator of Early Adaptation to the Mammalian Gut. Cellular Microbiology. 2018 Nov;20(11). 12890. https://doi.org/10.1111/cmi.12890
Znaidi, Sadri ; van Wijlick, Lasse ; Hernández-Cervantes, Arturo ; Sertour, Natacha ; Desseyn, Jean‐Luc ; Vincent, Frédéric ; Atanassova, Ralitsa ; Gouyer, Valérie ; Munro, Carol A. ; Bachellier-Bassi, Sophie ; Dalle, Frédéric ; Jouault, Thierry ; Bougnoux, Marie-Elisabeth ; d'Enfert, Christophe. / Systematic Gene Overexpression in Candida albicans identifies a Regulator of Early Adaptation to the Mammalian Gut. In: Cellular Microbiology. 2018 ; Vol. 20, No. 11.
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abstract = "Candida albicans is part of the human gastrointestinal (GI) microbiota. To better understand how C. albicans efficiently establishes GI colonization, we competitively challenged growth of 572 signature‐tagged strains (~10{\%} genome coverage), each conditionally overexpressing a single gene, in the murine gut. We identified CRZ2, a transcription factor whose overexpression and deletion respectively increased and decreased early GI colonization. Using clues from genome‐wide expression and gene‐set enrichment analyses, we found that the optimal activity of Crz2p occurs under hypoxia at 37°C, as evidenced by both phenotypic and transcriptomic analyses following CRZ2 genetic perturbation. Consistent with early colonization of the GI tract, we show that CRZ2 overexpression confers resistance to acidic pH and bile salts, suggesting an adaptation to the upper sections of the gut. Genome‐wide location analyses revealed that Crz2p directly modulates the expression of many mannosyltransferase‐ and cell‐wall protein‐encoding genes, suggesting a link with cell‐wall function. We show that CRZ2 overexpression alters cell‐wall phosphomannan abundance and increases sensitivity to tunicamycin, suggesting a role in protein glycosylation. Our study reflects the powerful use of gene overexpression as a complementary approach to gene deletion to identify relevant biological pathways involved in C. albicans interaction with the host environment.",
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author = "Sadri Znaidi and {van Wijlick}, Lasse and Arturo Hern{\'a}ndez-Cervantes and Natacha Sertour and Jean‐Luc Desseyn and Fr{\'e}d{\'e}ric Vincent and Ralitsa Atanassova and Val{\'e}rie Gouyer and Munro, {Carol A.} and Sophie Bachellier-Bassi and Fr{\'e}d{\'e}ric Dalle and Thierry Jouault and Marie-Elisabeth Bougnoux and Christophe d'Enfert",
note = "We are grateful to members of the genomics core facility (PF2, G{\'e}nopole) for the availability of the microarray scanner and the Alain Jacquier’s lab for making the GenePix software available. We are grateful to Drs. Suzanne Noble and Aaron Mitchell for providing C. albicans mutant collections. We thank all members of the Fungal Biology & Pathogenicity Unit, particularly Drs. Anne Neville and Adeline Feri for their numerous insights during the course of this project. This work has been supported by grants from the Agence Nationale de la Recherche (KANJI, ANR-08-MIE-033-01 to C.d’E. and F.D.; ERA-Net Infect-ERA, FUNCOMPATH, ANR-14-IFEC-0004; and CANDIHUB, ANR-14-CE-0018 to C.d’E.), the French Government’s Investissement d’Avenir program (Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases, ANR-10-LABX-62-IBEID to C.d’E.; Institut de Recherche Technologique BIOASTER, ANR-10-AIRT-03 to C.d’E., F.D. and T.J.), the European Commission (FinSysB PITN-GA-2008-214004 to C.d’E.) and the Wellcome Trust (The Candida albicans ORFeome project, WT088858MA to C.d’E. and C.M.). C.M. acknowledges support from the Medical Research Council, UK (New Investigator Award, G0400284), the MRC Centre for Medical Mycology (MR/N006364/1) and the University of Aberdeen. S.Z. is an Institut Pasteur International Network Affiliate Program Fellow. S.Z., L.v.W. and A.H.C. were the recipients of post-doctoral fellowships from the European Commission (FINSysB, PITN-GA-2008-214004 to S.Z.), the Agence Nationale de la Recherche (KANJI, ANR-08-MIE-033-01 to S.Z.; ERA-Net Infect-ERA, FUNCOMPATH, ANR-14-IFEC-0004 to A.H.C.; CANDIHUB, ANR-14-CE-0018 to L.v.W) and the French Government’s Investissement d’Avenir program (Institut de Recherche Technologique BIOASTER, ANR-10-AIRT-03 to S.Z. and A.H.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.",
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AU - Znaidi, Sadri

AU - van Wijlick, Lasse

AU - Hernández-Cervantes, Arturo

AU - Sertour, Natacha

AU - Desseyn, Jean‐Luc

AU - Vincent, Frédéric

AU - Atanassova, Ralitsa

AU - Gouyer, Valérie

AU - Munro, Carol A.

AU - Bachellier-Bassi, Sophie

AU - Dalle, Frédéric

AU - Jouault, Thierry

AU - Bougnoux, Marie-Elisabeth

AU - d'Enfert, Christophe

N1 - We are grateful to members of the genomics core facility (PF2, Génopole) for the availability of the microarray scanner and the Alain Jacquier’s lab for making the GenePix software available. We are grateful to Drs. Suzanne Noble and Aaron Mitchell for providing C. albicans mutant collections. We thank all members of the Fungal Biology & Pathogenicity Unit, particularly Drs. Anne Neville and Adeline Feri for their numerous insights during the course of this project. This work has been supported by grants from the Agence Nationale de la Recherche (KANJI, ANR-08-MIE-033-01 to C.d’E. and F.D.; ERA-Net Infect-ERA, FUNCOMPATH, ANR-14-IFEC-0004; and CANDIHUB, ANR-14-CE-0018 to C.d’E.), the French Government’s Investissement d’Avenir program (Laboratoire d’Excellence Integrative Biology of Emerging Infectious Diseases, ANR-10-LABX-62-IBEID to C.d’E.; Institut de Recherche Technologique BIOASTER, ANR-10-AIRT-03 to C.d’E., F.D. and T.J.), the European Commission (FinSysB PITN-GA-2008-214004 to C.d’E.) and the Wellcome Trust (The Candida albicans ORFeome project, WT088858MA to C.d’E. and C.M.). C.M. acknowledges support from the Medical Research Council, UK (New Investigator Award, G0400284), the MRC Centre for Medical Mycology (MR/N006364/1) and the University of Aberdeen. S.Z. is an Institut Pasteur International Network Affiliate Program Fellow. S.Z., L.v.W. and A.H.C. were the recipients of post-doctoral fellowships from the European Commission (FINSysB, PITN-GA-2008-214004 to S.Z.), the Agence Nationale de la Recherche (KANJI, ANR-08-MIE-033-01 to S.Z.; ERA-Net Infect-ERA, FUNCOMPATH, ANR-14-IFEC-0004 to A.H.C.; CANDIHUB, ANR-14-CE-0018 to L.v.W) and the French Government’s Investissement d’Avenir program (Institut de Recherche Technologique BIOASTER, ANR-10-AIRT-03 to S.Z. and A.H.C.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

PY - 2018/11

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N2 - Candida albicans is part of the human gastrointestinal (GI) microbiota. To better understand how C. albicans efficiently establishes GI colonization, we competitively challenged growth of 572 signature‐tagged strains (~10% genome coverage), each conditionally overexpressing a single gene, in the murine gut. We identified CRZ2, a transcription factor whose overexpression and deletion respectively increased and decreased early GI colonization. Using clues from genome‐wide expression and gene‐set enrichment analyses, we found that the optimal activity of Crz2p occurs under hypoxia at 37°C, as evidenced by both phenotypic and transcriptomic analyses following CRZ2 genetic perturbation. Consistent with early colonization of the GI tract, we show that CRZ2 overexpression confers resistance to acidic pH and bile salts, suggesting an adaptation to the upper sections of the gut. Genome‐wide location analyses revealed that Crz2p directly modulates the expression of many mannosyltransferase‐ and cell‐wall protein‐encoding genes, suggesting a link with cell‐wall function. We show that CRZ2 overexpression alters cell‐wall phosphomannan abundance and increases sensitivity to tunicamycin, suggesting a role in protein glycosylation. Our study reflects the powerful use of gene overexpression as a complementary approach to gene deletion to identify relevant biological pathways involved in C. albicans interaction with the host environment.

AB - Candida albicans is part of the human gastrointestinal (GI) microbiota. To better understand how C. albicans efficiently establishes GI colonization, we competitively challenged growth of 572 signature‐tagged strains (~10% genome coverage), each conditionally overexpressing a single gene, in the murine gut. We identified CRZ2, a transcription factor whose overexpression and deletion respectively increased and decreased early GI colonization. Using clues from genome‐wide expression and gene‐set enrichment analyses, we found that the optimal activity of Crz2p occurs under hypoxia at 37°C, as evidenced by both phenotypic and transcriptomic analyses following CRZ2 genetic perturbation. Consistent with early colonization of the GI tract, we show that CRZ2 overexpression confers resistance to acidic pH and bile salts, suggesting an adaptation to the upper sections of the gut. Genome‐wide location analyses revealed that Crz2p directly modulates the expression of many mannosyltransferase‐ and cell‐wall protein‐encoding genes, suggesting a link with cell‐wall function. We show that CRZ2 overexpression alters cell‐wall phosphomannan abundance and increases sensitivity to tunicamycin, suggesting a role in protein glycosylation. Our study reflects the powerful use of gene overexpression as a complementary approach to gene deletion to identify relevant biological pathways involved in C. albicans interaction with the host environment.

KW - Candida albicans

KW - gastrointestinal colonization

KW - signature-tagged overexpression

KW - transcriptomics

KW - chromatin immunoprecipitation-on-chip

KW - regulatory networks

KW - CRZ2

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DO - 10.1111/cmi.12890

M3 - Article

VL - 20

JO - Cellular Microbiology

JF - Cellular Microbiology

SN - 1462-5814

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